The main objective of this project is to characterize the relationship between Extracellular Signal-Regulated Kinase 1/2 (ERK) and cAMP Response Element-Binding Protein (CREB) activity in the extended amygdala and the nucleus accumbens (NAC) core in a long-lasting, stress-related murine model of depression. Although these regions have long been implicated as major substrates for affective, emotional, hedonic, and motivated behavior in humans, little is known about how long-term stress, a major risk factor for depression, disrupts regional activity and connectivity between these and cortical regions to produce depressive-like behaviors consistent with depression in humans. The proposed studies should yield two types of information: First, independent analyses of ERK1/2 and CREB activity (by Western blot) in the sub-regions of the extended amygdala and NAC core will elucidate the role of the signaling pathway in appetitive events that rely on hedonic and motivated processing. A novel, long-lasting model of depression developed and behaviorally characterized in the laboratory will then allow for the investigation of the intracellular mechanisms by which the persistent depressive-like state and antidepressant treatment influence the extended amygdala and NAC core to regulate hedonically-driven and motivated behaviors. We hypothesize the depressive-like phenotype will be characterized by modulated ERK and CREB activity in a regionally-specific manner that co-varies with behavioral outcomes; antidepressant treatment is hypothesized to restore normal ERK/CREB activity. Finally, viral-mediated, local manipulations of CREB are hypothesized to restore motivated responding in depressive animals exposed to prior CORT in a fashion similar to that of antidepressant drugs. Every year, 9.5% of the adult American population will suffer from a depressive illness. Depression carries immense economic, social, and personal costs; however, the manner in which depression impairs mood and motivation is not entirely understood, and contemporary antidepressant drugs are no more effective in treating depression than were first-generation antidepressants developed 50 years ago. Only when the scientific community more fully understands the biological mechanisms of the disease will the medical community be better equipped to rapidly treat depression in patients. [unreadable] [unreadable] [unreadable] [unreadable]